Tricyclic benzodiazepines

ABSTRACT

Tricyclic benzodiazepine derivatives (A) bearing a heterocyclic ring joined between positions 4 and 5 of the benzodiazepine moiety are described. The heterocyclic ring will contain the nitrogen atom appearing at position 4 of the benzodiazepine ring as well as the hetero atom, which may be either oxygen or nitrogen, attached to the carbon atom at the 5-position of the benzodiazepine ring. A bearing an oxygen atom in the new heterocyclic ring may be formed from the corresponding 4,5unsaturated benzodiazepines by treatment with an epoxide compound in the presence of an acid catalyst. A bearing either a nitrogen or an oxygen atom in the new heterocyclic ring may be prepared by cyclization of the corresponding open compound. A are useful as sedative, muscle relaxant and anti-convulsant agents.

United States Patent [191 Derieg et al.

[ Sept. 16, 1975 TRICYCLIC BENZODIAZEPINES [73] Assignee: Hoffmann-La Roche Inc., Nutley,

22 Filed: Apr. 6, 1970 211 App]. No.: 26,068

Related US. Application Data [63] Continuation-impart of Ser. No. 863,377, Oct. 2, I969, abandoned, which is a continuation-in-part of Ser. No. 768,909, Oct. 18, I968, abandoned.

[52] US. Cl 260/239.3 T; 260/244 R; 260/256.4 F; 260/295 T; 260/296 T;

[51 Int. Cl. C07D 487/04; C07D 498/04 [58] Field of Search 863;377/; 768/909; 260/239.3 T, 243, 244, 256.4 F, 307, 309.7

Primary Examiner-Norma S. Milestone Assistant Examiner--Robert T. Bond Attorney, Agent, or Firm-Samuel L. Welt; Bernard S. Leon; Frank P. Hoffman [5 7 1 ABSTRACT Tricyclic benzodiazepine derivatives (A) bearing a heterocyclic ring joined between positions 4 and 5 of the benzodiazepine moiety are described. The heterocyclic ring will contain the nitrogen atom appearing at position 4 of the benzodiazepine ring as well as the hetero atom, which may be either oxygen or nitrogen, attached to the carbon atom at the 5position of the benzodiazepine ring. A bearing an oxygen atom in the new heterocyclic ring may be formed from the corresponding 4,5-unsaturated benzodiazepines by treatment with an epoxide compound in the presence of an acidcatalyst. A bearing either a nitrogen or an oxygen atom in the new heterocyclic ring may be prepared by cyclization of the corresponding open compound. A are useful as sedative, muscle relaxant and anticonvulsant agents.

22 Claims, N0 Drawings droxyl group from an organic acid, such as an alkanoic acid containing from 2-7 carbon atoms, for example propionyl and the like. The term lower alkoxy comprehends a lower alkyl group having an oxygen funcrmcvcuc BENZODIAZEPINES CROSS REFERENCE To RELATED 5 tion substituted therein, such as methoxy, ethoxy, APPLICATIONS propoxy, etc. The term halogen represents all four The application is a continuation-in-part of Ser. No. forms thereof, i.e., fluorine, chlorine, bromine and io- 863,377, filed Oct. 2, 1969, which in turn is a continuadine, unless expressly indicated otherwise. The term tion-in-part of Ser. No. 768,909, filed Oct. 18, 1968, lower alkanol connotes primary, secondary, or terboth applications now abandoned. tiary saturated aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and the like.

DESCRIPTION OF THE NVENTION A preferred group of compounds falling within the The present invention relates to tricyclic benzodiazescope of formula I are those wherein the hetero atom Z pines of the following formula is oxygen, i.e., compounds of the formula C H 2 RH c H 2 n I1 wherein A is selected from the group consisting of wherein A, R -R and n are as described above. CH and Another preferred embodiment of the present invention encompasses the compounds of formula I wherein O the hetero atom Z is oxygen and wherein'R is selected II from the group consisting of hydrogen, halogen, nitro, C trifluoromethyl, or lower alkyl, i.e., compounds of the formula Z is a hetero atom selected from the group consisting of -O and R" 40 1 L ,L

R where R 15 hydrogen, lower alkyl or acyl; n is an mte- 1 I-b ger from l to 2; R is hydrogen, halogen, nitro, trifluo- R romethyl, lower alkyl, lower alkyl mercapto or lower 3 alkoxy; R is hydrogen, lower alkyl, [cyclo-lower al- R5 0 kyl]-lower alkyl, lower alkoxy-lower alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower al- RK kylamino-lower alkyl or di-lower alkylamino-lower alkyl; R is hydrogen, lower alkyl or the group -COO- lower alkyl; R is hydrogen, lower alkyl or CH X where X is selected from the group consisting of chlorine, bromine, lower alkoxy, lower alkoxy-lower alkyl wherein R is selected from the group consisting of hyand di-lower alkylamino; and R is hydrogen, lower al drogen, halogen, nitro, trifluoromethyl, and lower alkyl, pyridyl, phenyl and phenyl substituted with a memkyl; A, n, and R -R are as described above.

her selected from the group Consisting of halogen, ni-- A further preferred embodiment of the present intro, trifluoromethyl, and lower alkyl. vention encompasses the compounds of formula 1 As used herein, the term lower alkyl, either alone wherein the hetero atom Z is oxygen, R is hydrogen or or in combination as in di-lower alkylamino, compre- ,0 halogen, with chlorine being the preferred halogen, and hends straight or branched chain hydrocarbon groups is joined to the benzodiazepine moiety at the 7-position having from l7 carbon atoms, preferably l-4 carbon thereof; R is hydrogen, lower alkyl, with methyl preatoms, such as methyl, ethyl, propyl, isopropyl and the ferred, or hydroxy-lower alkyl, with B-hydroxy ethyl like. The term [cyclo-lower alkyl]-lower alkyl enpreferred; R is hydrogen; R is hydrogen, lower alkyl, compasses hydrocarbon groups having 46 carbon 5 most preferably methyl, or chloromethyl; and R is atoms, such as cyclopropylmethyl, cyclobutylmethyl, phenyl or phenyl substituted at. the ortho position with cyclopropylethyl and the like. The term acyl encomhalogen, with fluorine being the most preferred halopasses an organic radical derived by removal of a by gen; i.e., compounds of the formula wherein R is hydrogen or halogen; A and n are as described above; R is hydrogen, lower alkyl or hydroxy lower alkyl; R, is hydrogen, lower alkyl, or chloromethyl; and R is hydrogen or halogen.

Most preferred among the compounds of formula I above are those wherein the hetero atom Z is oxygen; n is 1; R is chlorine and is joined to the benzodiazepine moiety at the 7-position thereof; R is hydrogen, methyl or B-hydroxy ethyl; R is hydrogen; R is hydrogen, methyl or chloromethyl; and R is phenyl or phenyl substituted in the ortho position with fluorine.

Another particular aspect of the present invention relates to compounds of formula 1 above wherein where R is hydrogen, lower alkyl or acyl, i.e., compounds of the formula wherein A, n, and R -R are as described above.

Still another particular aspect of the present invention relates to compounds of formula 1 above wherein A represents the group CH i.e., compounds of the formula N R3 s X (cazln wherein Z, n, and R -R are as described above.

4 Yet another particular aspect of the present invention relates to compounds of formula 1 above wherein A represents the group Z is oxygen, R is hydroxy lower alkyl, and n, R R R and R are as described above; or A is Z is oxygen, R is the group -CH X where X is chlorine, bromine, lower alkoxy-lower alkyl or di-lower alkylamino and R R R R and n are as described above; or A is Z is oxygen, R is hydrogen, lower alkyl or pyridyl, and R R R R and n are as described above.

Compounds of formula 1 above wherein the hetero atom Z is oxygen and n is l are conveniently prepared by reacting a 4,5-unsaturated 1,4-benzodiazepine of the following formula N A H R II wherein R R R R and A are as described above with an epoxide compound of the formula CH CH- R,

Ill

wherein R is as described above in the presence of an acidic agent, such as, for example, an aprotic acid, e.g., aluminum chloride, ferric chloride, zinc chloride, titanium tetrachloride, boron trifluoride, etc.; or p-toluene sulfonic acid, benzene sulfonic acid, and the like. The most preferred acidic agent for the purposes of this invention is aluminum chloride. Examples of compounds of formula III useful in this invention include ethylene oxide, propylene oxide, l-chloro-2,3-epoxy propane,

etc.

The reaction whereby compounds of formula I above wherein Z is oxygen and n is 1 are prepared from the compounds of formulae II and III is conveniently conducted in the presence of an anhydrous inert organic solvent. Suitable inert organic solvents for this purpose include, for example, aromatic hydrocarbons such as benzene, toluene, xylene, etc., ethers, such as tetrahydrofuran and diethyl ether, or carbon di-sulfide. This reaction may be carried out at a temperature in the range of from about -10 to the reflux temperature of the reaction medium, most preferably from 10 to the reflux temperature. The selection of temperature is not critical for the purposes of the present invention and will, of course, depend upon the characteristics of the compounds selected as reagents, the solvent medium employed and the nature of the acidic agent used.

The compounds of formula ll above wherein R is hydrogen, lower alkyl, [cyclo-lower alkyl]lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl and di-lower alkylamino-lower alkyl are readily prepared in a manner known in the art. The compounds of formula II above wherein R is lower alkoxy-lower alkyl can be prepared by reacting a compound of formula ll wherein R is hydrogen with a halo-di-lower alkyl ether.

It should be noted that compounds of formula III above may, in addition to forming the heterocyclic ring between the 4 and 5 positions of the benzodiazepine moiety upon reaction with the compound of formula II, also react with the nitrogen atom in the l-position of the compounds of formula II when the nitrogen is unprotected, that is when R is hydrogen. Thus, the reaction of a compound of formula ll wherein R is hydrogen with a compound of formula II] can result in a mixture of compounds, the first showing no substitution on the l-nitrogen and the second showing alkylation of the l-nitrogen. For example, if a compound of formula ll wherein R is hydrogen is reacted with a compound of formula III wherein R is hydrogen, i.e. ethylene oxide, one is able to isolate from the reaction mixture both the corresponding compound of formula I above wherein R is hydrogen and the corresponding compound of formula I above wherein R is ,B-hydroxy ethyl. By controlling the reaction conditions, alkylation of the lnitrogen can be avoided.

It would appear that when a compound of formula III is reacted with a compound of formula ll, the R bearing carbon atom can be attached relative to the benzodiazepine ring in one of two alternate positions, depending upon the point where the epoxide ring cleaves during the reaction. However, experimentation has shown that the epoxide ring evidences a propensity to favor cleavage between the oxygen and the unsubstituted carbon atom. Thus, when cleavage occurs at this point, the carbon atom bearing the R substituent is bonded to the oxygen atom in the heterocyclic ring.

Thus, the reaction between the compounds of formulae ll and Ill as described above produces the compounds of Formula I wherein Z is oxygen, n is l, and the R substituent is joined to the 2-position of the heterocyclic ring, i.e., compounds of the formula R1 I-f 6 wherein R -R and A are as described above.

In a further process aspect of the present invention, compounds of formula 1 above are conveniently prepared by reacting a corresponding 2-substituted aminophenyl ketone of the formula wherein R R R R and A are as described above and X is chlorine, bromine or iodine with a diamine or aminoalkanol of the general formula wherein R n and Z are as described above.

The reaction between the compounds of formulae IV and V above is conducted in a reaction medium containing a base and an inert organic solvent at a temperature in the range of from about 25C. to the reflux temperature of the reaction medium, preferably at about the reflux temperature. Suitable bases for the purposes of this invention are inorganic bases, such as sodium acetate, and organic bases such as the tertiary amines, for example, trialkylamines, with triethylamine and pyridine being preferred. A variety of organic solvents are useful for the purposes of this invention. Among these suitable solvents are lower alkanols, such as methanol, ethanol, propanol, etc., with ethanol being preferred; aromatic alcohols, such as benzene, toluene, xylene, etc.; high boiling point ethers, such as tetrahydrofuran and dioxane; and amides, such as dimethylformamide, diethylformamide and the like. Examples of compounds of formula V useful in this inven- 'tion include 2-aminoethanol, ethylenediamine, 3-

aminopropanol, etc.

The compounds of formulae 1V and V above are readily prepared in a manner known in the art. It should be noted that in preparing the compounds of formula IV above wherein R is hydroxylower alkyl following known techniques, it is expedient to first protect the hydroxyl group present in the ketone starting material before introducing the substituent, A, R;, and X being defined as above, into the molecule. By so-protecting the hydroxyl group, one can avoid unwanted side reactions and unwanted side products which of necessity render the reaction less efficient. Suitable protecting groups for the purpose include the acyl moiety of a lower alkanoic acid such as acetyl, propionyl and the like or carbobenzoxy. Following preparation of the formula IV compound and completion of the reaction between the compounds of formulae IV and V above, the protecting group can then be split off. The splitting off of the protecting group can be effected by conventional techniques, for example, by alkaline hydrolysis. The alkaline hydrolysis is expediently carried out in the presence of an inert solvent. Suitable bases include alkali-hydroxides or alkaline earth metal hydroxides, such as sodium hydroxide, calcium hydroxide and the like.

If, in the compounds of formula IV, X is chlorine or bromine, the reaction mixture may also contain sodium iodide in order to exchange the X substituent for the more reactive iodine atom which then is removed in the ensuing reaction.

The compounds of formula I wherein the hetero atom Z is and R6 is lower alkyl or acyl are prepared from the corresponding compounds of formula I wherein Z is and R,- is hydrogen by conventional alkylation or acylation procedures. By controlling the reaction conditions alkylation or acylation can be accomplished on the nitrogen of the heterocyclic ring without affecting other vulnerable positions on the benzodiazepine moiety.

The reaction path described above for the cyclization process to prepare compounds of formula I is believed to proceed via an intermediate of the following proposed structure wherein R -R A, Z and n are as described above which need not be isolated from the reaction mixture as it cyclizes to the desired compounds of formula I under the reaction conditions employed. By using less energetic reaction conditions, the compounds of the formula VI can be isolated and subsequently cyclized to the desired product. However, in a preferred embodiment, the intermediate is not isolated but is permitted to cyclize in the reaction medium in which it is prepared. 1

It has been found that in following both the epoxide method, involving the reaction between compounds of formulae II and III, and the cyclization method, involving the reaction between compounds of formulae IV and V, discussed above for the preparation of the tricyclic benzodiazepine derivatives of formula I, the product obtained in many cases will be a mixture of epimers, That is to say in many instances both synthetic routes produce a mixture of compounds that differ from one another only in the way the atoms are oriented in space but are like one another with respect to which atoms are attached to which other atoms. Thus, for example, in the preparation of the compounds of formula I wherein Z is oxygen, R is chlorine joined to the benzodiazepine ring at the 7-position thereof, R and R are hydrogen, A is carbonyl, n is 1, R is methyl oined to the heterocyclic ring at the 2-position, and R is phenyl, Le, a compound of the formula H i N and (2,11b cis) (2,11b trans) The epimerization that occurs during this reaction to produce'the two epimers is considered to proceed by way of a heterolytic cleavage giving an intermediate represented by theformula n i N f 01 N In a further process aspect of the present invention, a hydroxy-lower alkyl group, a lower alkoxy-lower alkyl. group, an amino-lower alkyl group, a mono-lower alkylamino-lower alkyl group or a di-lower alkylaminolower alkyl group can be introduced as the R substituent into a compound of formula I above wherein R is hydrogen by reacting said compound with a suitable alkylating agent. Thus, one can prepare a compound of the formula l ii 1' wherein R is hydroxy-lower alkyl, lower alkoxy-lower alkyi, amino-lower alkyl, monolower alkylamino-lower alkyl or di-lower alkylamino-lower alkyl; and R R -R A, Z and n are as described above by first preparing the l-sodio derivative of a compound of the formula Ri (cm wherein wherein m is a whole integer from 2 to 7, R and R are selected from the group consisting of hydrogen and lower alkyl and X is a halogen atom selected from the group consisting of chlorine, bromine and iodine. Representative of such alkylating agents are 2bromoethanol, 3-bromopropanol, chlorodi-' methyl ether, bromo-diethyl ether, (Z-bromoethyl)dimethylamine, 3-bromopropylamine, (2- bromoethyl) diethylamine.

The l-sodio derivative of a compound of formula l-g above can be prepared by treating said compound with a sodium lower alkoxide, such as sodium methoxide or with sodium hydride. This reaction is expediently effected in the presence of an inert organic solvent such as dimethylformamide (DMF), aromatic hydrocarbons, i.e., benzene, toluene and the like, with DMF being the preferred solvent. For the purposes of this reaction, temperatures above and below room temperature may be employed. In a preferred embodiment temperatures between about 0 and 10C. are utilized.

The alkylation of the l-sodio derivative of a compound of formula I-g above is expediently effected in the presence of an inert solvent such as DMF, aromatic hydrocarbons, i.e., benzene, toluene and the like, with DMF being the preferred solvent. This alkylation reaction may be effected using temperatures above and below room temperature, with temperatures between about 10C. and room temperature being preferred.

In a further process aspect of the present invention, a compound of formula I above wherein R is halogen and R is hydroxy-lower alkyl, i.e., a compound of the formula [lliydroxylower alkyl] N A i 3 halogen I m an,

wherin R -R A, Z and n are as described above may be prepared by reacting the l-so dio derivative of a compound of the formula haloge Lh wherein R -R A, Z and n are as described above with a compound of the formula X-(CH ),,COO-lower alkyl VllI wherein X is a halogen atom selected from the group consisting of chlorine, bromine and iodine and n is a whole integer from l-7 and without isolation, reducing; the ester derivative soobtained with a suitable reducing agent such as lithium aluminum hydride.

Representative of the compounds of formula VI" suitable for the process are ethyl bromoacetate, ethyl 3-bromopropionate, and the like. The l-sodio derivative of the compound of formula l-h can be prepared, as described hereinbefore. The esterification reaction is expediently effected in the presence of an inert solvent such as DMF.

Examples of compounds which correspond to formula l and which are thus representative of the present invention maybe listed as follows:

lO-Chloro-7-( 2-hydroxyethyl )-2,3 ,5 ,l lb-tetrahydrol lb-phenyloxazolo[ 3,2-d][ 1 ,4]benzodiazepin-6- (7l-l)-one;

lO-Chloro-l lb-( 2-fluorophenyl )-2,3 ,5 ,l lb-tetrahydrooxazolo[3,2-d][ l ,4] benzodiazepin-6-(7H)-one;

lO-Chloro-l lb-( 2-fluorophenyl )-7-( 2-hydroxyethyl)-2,3 ,5 ,1 lb-tetrahydro-ocazolo[ 3 ,2,-

d] l ,4]benzodiazepin-6-( 7H )-one;

lO-Chloro-7-methyl-2,3 ,5 ,1 lb-tetrahydro-l lbphenyloxazolo[3,2-d][ l,4]benzodiazepin-6-(7lH)-one; lO-Chloro-2,7-dimethyl-2,3,5 ,1 lb-tetrahydro-l lbphenyloxazolo[3,2-d][ l ,4]benzodiazepin-6(7H )-one (2,1 lb cis);

lO-Chloro-2-chloromethyl-2,3 ,5 ,l lb-tetrahydro-7- methyl-l lb-phenyloxazolo[ 3,2-d][ 1,4]benzodiazepin6(7l-l)-one;

lO-Chloro-7-methyl-2,3 ,5 ,6,7 ,l lb-hexahydro-l lbphenyloxazolo[ 3,2-d][ 1,4]benzodiazepine;

lO-Chloro-l ,2,3,5 ,7,l lb-hexahydro-7-methyl-l lbphenyl-6H-imidazo l ,2-d][ l,4]benzodiazepin-6-one;

l l-Chloro-3,4,6,7,8,l 2b-hexahydro-8-methyl-12bphenyl2l-l-[ 1,3 ]oxazino[ 3 ,2-d[[ 1,4]benzodiazepine;

l-Chloro-2,3,5,6,7,l lb-hexahydro-7-methyl-l lbphenyl-l H-irhidazo[ l ,2-d 1,4]benzodiazepine;

lO-Chloro-2,3 ,5 ,l lb-tetrahydro-Z-methyl-l lbphenyloxazolo[ 3,2-d][ l,4]benzodiazepin-6(7H)-one (2,1 1b cis);

lO-Chloro-2,3 ,5,1 lb-tetrahydro-Z-methyl-l lbphenyloxazolo[3,2-d l ,4]benzodiazepin-6(7H)-one (2,1 lb trans);

10-Chl0r0-2 ,3 ,5 ,1 lb-tetrahydro-3-methyl-l 1bphenyloxazolo[3,2-d][ l ,4]benzodiazepin-6(7ll)- one (3,1 lb cis).

The tricyclic benzodiazpine derivatives of formula 1 above are useful as pharmaceuticals and are characterized by activity as sedative, muscle relaxant and anticonvulsant agents. These compounds can be used in the form of conventional pharmaceutical preparations; for example, the aforesaid compounds can be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as for example, water gelatin, lactose, starch, magnesium stearate, talc, vegetable oil, gums, polyalkylene glycols, Vaseline or the like. They can be administered in conventional pharmaceutical forms, e.g., solid forms, for example, tablets, dragees, capsules, suppositories or the like, or in liquid forms, for example, solutions, suspensions or emulsions. Moreover, the pharmaceutical compositions containing compounds of this invention can be subjected to conventional pharmaceutical expedients such as sterilization, and can contain conventional pharmaceutical excipients such as preservatives, stabilizing agents, wetting agents, emulsifying agents, salts for the adjustment of osmotic pressure, or buffers. The compositions can also contain other therapeutically active materials.

A suitable pharmaceutical dosage unit can contain from about 1 to about 500 mg of the aforesaid compounds of formula 1; with a dosage range of from about 1 mg to about 100 mg being the preferred oral administration and a dosage range of from about 1 mg to about 50 mg being preferred for parenteral administration. However, for any particular subject, the specific dosage regimen should be adjusted according to individual need and the professional judgment of the person administering or supervising the administration of the aforesaid compounds. it is to be understood that the dosages set forth herein are exemplary only and that EXAMPLE 1 Preparation of 10-chloro-2,3 ,5-1 lb-tetrahydrol lb-phenyloxazolo [3,2-d][ l,4]benzodiazepin-6-( 7H)-one To 5 gm. (18.5 mmole) of 7-chloro-l,3-dihydro-5- phenyl-Zl-l-1,4-benzodiazepin-2-one in ml. of dry benzene was added 5.0 g. (37 mmole) of aluminum chloride. The reaction mixture was stirred 6 hours at reflux, cooled to room temperature and treated with 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was stirred 18 hours, the benzene was then removed and the residue was treated with aqueous ammonium hydroxide and ml. of methylene chloride. The resulting precipitate was removed by filtration. The organic layer was then separated, washed with brine, dried and the solvent evaporated to yield a residue which was crystallized from ether and recrystallized from methylene chloride-hexane to give the above-titled product as colorless prisms, mp. -135 and then resetting, m.p. 173l77.

EXAMPLE 2 Cl W Preparation of lO-chloro-7-( 2-hydroxyethyl )-2,3 ,5 ,l lb-tetrahydrol l.b-phenyloxazolo[ 3,2-d][ l ,4]benzodiazepin-6- (7l-l)-one Preparation of l-chloro-l 1b-( 2-fluorophenyl )-2,3 ,5 ,1 lb-tetrahydrooxazolo[3,2-d][ 1 ,4]benzodiazepin-6-( 7H )-one fil To g. (51.9 mmole) of 7-chloro-5-(2-fluorophenyl )-l ,3-dihydro-2H-l ,4-benzodiazepin-2-one in 150 ml. of dry benzene, 9 g. (67.7 mmole) of aluminum chloride was added and stirring was continued 15 minutes. The reaction mixture was cooled in an ice bath and 8.8 g. (0.2 mole) of ethylene oxide was added dropwise. After 18 hours of stirring at room temperature, the reaction mixture was heated to 40 for l-hour and then cooled to room temperature and treated with 5 g. (37.6 mmole) of aluminum chloride, followed by 4.4 g. (0.1 mole) of ethylene oxide. The reaction mixture was heated 4 hours at 45 50 and then evaporated to dryness. Methylene chloride, ice and ammonium hydroxide were added and the solid removed by filtration. The filtrate was separated and the organic phase reduced to dryness in vacuo. The residue was dissolved in dilute hydrochloric acid and the pH of the solution adjusted to 5 with ammonium hydroxide. The acidic solution was washed with ether, made basic and extracted with methylene chloride. The organic phase was washed with brine, dried and evaporated to dryness. Recrystallization from methylene chloride-hexane gave the above-titled product as colorless rods, m.p. l83l84.

EXAMPLE 4 Preparation of lO-chloro-l 1b-( 2-fluorophenyl )-7-( 2-hydroxyethyl 2,3,5,l lb-tetrahydrooxazolo[ 3,2-d][ 1,4]benzodiazepin-6(7H)-one cn cn ou The ether wash in Example 3 of the said solution at pH 5 was evaporated to dryness, dissolved in methylene chloride and chromatographed over 200 g. of silica gel with methylene chloride and ethyl acetate which fractions were combined and the solvents removed to give crude product. Recrystallizations from methylenechlo ride petroleum ether gave the above-titled product as colorless plates, m.p. l47l5 1.

EXAMPLE 5 o C6145 Q Method A A mixture of ml. of dried benzene and 5.0 g. of aluminum chloride under a dry ice-acetone filled condenser was stirred and treated with 10.0 g. (35 mmole) of 7-chlorol ,3 dihydro-1-methyl-5-phenyl-21-l-l ,4- benzodiazepin-2-one giving a yellow solid. Stirring was continued for 20 minutes and after the addition of 35 ml. of hexane, the mixture was cooled in an ice-bath. Upon the addition of 7 ml. of ethylene oxide, the yellow solid dissolved. The reaction mixture was warmed to room temperature and was stirred overnight. The benzene solution was repartitioned between methylene chloride and iced aqueous ammonium hydroxide. Filtration removed a large portion of the aluminum salts and the organic layer was separated, washed with water, dried and evaporated. The resultant residue was washed with ether to give the above-titled product as colorless crystals, m.p. l79184. Two recrystallizations from methylene chloride-hexane gave colorless rods, m.p. l82l84.

Method B EXAMPLE 6 Preparation of l0-chloro-2,7-dimethyl-2,3 ,5 Il lb-tetrahydro-l lbphenyloxazolo[3 ,2-d][1 ,4]benzodiazepin-6(7H)-one (2,1 lb cis) CGHS A mixture of 10.0 g. (35 mmole) of 7-chloro-l,3 dihydro-l-methyl-S-phenyl-ZH-1.4-benzodiazepin- 2-one, 6.7 g. of aluminum chloride, 300 ml. of benzene and ml. of hexane was chilled in an ice-bath and was treated with 10 ml. of propylene oxide. The reaction mixture was warmed to room temperature and was stirred overnight. Work-up as in Method A, Example 5, yielded a mixture of the epimers of lO-chloro-2,7- dimethyl-2,3 ,5 ,l lb-tetrahydro-l lb-phenyloxazolo[3,2-d][l,4]benzodiazepin-6(7H)one. A solution of 1.0 g. of this mixture was stirred overnight at 80 in 25 ml. of boron trifluoride etherate. The reaction mixture was poured carefully into ice water and made basic with ammonium hydroxide. The mixture was extracted with chloroform, water washed, dried and concentrated to a solid residue. Three recrystallizations from methylene chloride-hexane gave the abovetitled isomer, m.p. l42l43.

EXAMPLE 7 Preparation of lO-chloro-2-chloromethyl-2,3,5,l lb-tetrahydro-7- methyl-l lb-phenyloxazolo[ 3,2-d][ 1,4]benzodiazepin- 6(7H)-one Tll EXAMPLE 8 Preparation of .lOchloro-7-methyl-2,3,5,6,7,l lb-hexahydro-l lbphenyloxazolo[ 3,2-d][ 1,4]benzodiazepine C ll Method A A mixture of 12.5 g. (46 mmole) of 7-chloro-2,3-

dihydrol -methyl-5 -phenyll H- l ,4-benzodiazepine hydrochloride, 5.0 g. of aluminum chloride, 200 ml. of benzene and 30 ml. of hexane was stirred for 20 minutes, chilled in an ice-bath and then treated with 7.0 ml. of ethylene oxide. The reaction mixture was warmed to room temperature andstirred overnight. The benzene was removed by evaporation and the residue was partitioned between methylene chloride and dilute ammonium hydroxide. The solid was removed by filtration and the organic layer washed with water, dried and evaporated to give an orange oil. Upon standing, the oil crystallized and the resultant solid was recrystallized from hexane to give the above-titled product. An analytical sample was obtained as colorless prisms, m.p. lO9l 10, by recrystallization from ether.

Method B A solution of 5.6 g. (18.2 mmole) of 5-chloro-2-(2- chloroethylmethylamino)benzophenone, 5.0 g. of sodium iodide, 50 ml. of 2-aminoethanol, 50 ml. of triethylamine and ml. of ethanol was heated at reflux for 17 hours. The reaction mixture was poured into ice water and was extracted with methylene chloride. The organic phase was washed with water, dried and evaporated to an oil. The oil was cooked out with petroleum ether and the above-titled product crystallized from the solvent, m.p. lO7-109.

EXAMPLE 9 Preparation of lO-chloro-l ,2,3,5,7,l lb-hexahydro-7-methyl-l lb-phenyl-6l-I-imidazo[ l ,2-d][ 1,4]benzodiazepin-6-one A solution of 6.4 g. (20 mmole) of 2-(2-chloro-N- methylacetamido)5-chlorobenzophenone, 12.0 g. (0.2 mole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was heated at reflux for 20 hours. The reaction mixture was concentrated to a residue which was partitioned between ether and water. The ether layer was washed with water, dried and concentrated to a small amount of liquid which was treated with a small amount of ethanol to give upon standing the above-titled product as colorless crystals, m.p. 164l67.

EXAMPLE lO Preparation of l l-chloro-3,4,6,7,8, l 2b-hexahydro-8-methyll 2b-phenyl-2H-[ l ,3]oxazino[3,2-d][ l ,4]benzodiazepine A solution of 5.0 g. (16 mmole) of -chloro-2(2- chloroethylmethylamino)benzophenone, 3.75 g. (50 mmole) of 3-aminopropanol, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The reaction mixture was then evaporated to a residue which was washed with water, dissolved in methylene chloride and chromatographed over a column of Florisil. The first fraction yielded the recovery of 2.7 g. of starting material. Elution with acetone, ethanol, methanol and finally with ammonial methanol gave a compound of very low Rf on fluorescent silica eluted with ethanol. Crystallization from acetone and recrystallizations from ether-petroleum ether gave the above-titled product as colorless prisms, m.p. l42l44.

EXAMPLE 1 1 Preparation of -chloro-2,3,5,6,7,1 lb-hexahydro-7-methyl-l lb-phenyl-ll-l-imidazo[1,2-d][ 1,4]benzodiazepine N 65 mg A solution of 5.0 g. (16 mmole) of 5-chloro-2-(2- chloroethylmethylamino)benzophenone, 3.0 g. (50 mmole) of ethylenediamine, 50 ml. of triethylamine and 250 ml. of ethanol was stirred at reflux for 48 hours. The solvents were removed by evaporation and the residue containing starting material and the product was washed with water, chromatographed over Florisil, and recrystallized from petroleum ether to give the above-titled product as yellow prisms, m.p. l00l02.

EXAMPLE 12 Preparation of 10-chloro-2,3,5,l lb-tetrahydro-Z-methyl-l 1bphenyloxazolo[3,2-d][ 1,4lbenzodiazepin-6(7H)-one (2,1 lb trans) A solution of 67 g. (0.19 mole) of 2-( 2- bromoacetamido)-5-chloro-benzophenone, 500 ml. of xylene, 15.7 g. (0.21 mole) of l-amino-2-propanol and 25 ml. of triethylamine was stirred at reflux for hours. The reaction mixture was concentrated in vacuo to a residue which was partitioned between methylene chloride and water. The organic layer was washed with water, dried and concentrated to an oil which was crystallized from ethyl acetate to give 18.3 g. ofa colorless solid, m.p. l81-l84. Thin layer chromatography on Eastman alumina plates with an eluant of 3 parts of hexane and 2 parts of ethyl acetate revealed the presence of two compounds. The product was dissolved in chloroform and chromatographed over Woelm neutral alumina I. A mixture concentrated in the above-titled product (the faster of the two compounds) was col- 18 lected in 30% ethyl acetate-% hexane. Recrystallizations from methylene chloride gave colorless prisms, m.p. 188-189.

EXAMPLE 1 3 Preparation of 10 -chloro-2,3 ,5 ,1 lb-tetrahydro-2-methyl-l lb-phenyloxazolo[3,2-d][1,4]benzodiaz-epin-6(7H)-one (2,1 1b cis) A 1.0 g. sample (0.3 mmol) of the two-compound mixture obtained in Example 12 was stirred 17 hours at in a solution with 25 ml. of boron trifluoride etherate. The reaction mixture was poured over 200 g. of ice and was carefully treated with ammonium hydroxide to give a pH of 8. The resultant solid was removed by filtration and was air dried to give the above-titled product. Two recrystallizations from chloroform-hexane gave colorless prisms, m.p. 172174.

EXAMPLE 14 Preparation of a mixture of l0-chloro-2,3,5,l lb-tetrahydro-2-methyl-l lbphenyloxazolo[3,2-d][1 ,4]benzodiazepin-6( 7H)one (2,11b cis) and lO-chloro-2,3,5,1 1b-tetrahydro-2-methyl-l lbphenyloxazolo[3,2-d][ l ,4]benzodiazepin-6( 7H)-one (2,11b trans) Method A To a solution of 35.26 g. (0.1 mole) of 2-(2- bromoacetamido)-5-chlorobenzophenone, 100 ml. of triethylamine and 600 ml. of ethanol, -22.5 g. (0.3 mole) of l-amino-Z-propanol was added. The reaction mixture was stirred at room temperature for 65 hours. The solvent was removed in vacuo and the residue par titioned between water and ethyl acetate. The organic layer was dried and concentrated to give a colorless oil. An ether solution of the oil was treated with dry hydrogen chloride to form the hydrochloride salt which was recrystallized from ethanol to give colorless prisms of 5-chloro-2[2-(2-hydroxypropylamino)-acetamido]- benzophenone, m.p. l94-195.

A pyridine solution of 8.0 g. (23 mmol) of 5-chloro- 2[2-(2-hydroxypropylamino)acetamido]benzophenone was stirred 17 hours at reflux in the presence of 0.5 g. of pyridine hydrochloride. The reaction mixture was concentrated in vacuo to a. residue which was crys tallized from ethanol as colorless crystals, m.p. l84-l 85. The product is a mixture of the above-titled compounds in about equal portions.

In a similar fashion, 5-chloro-2[2-(2-hydroxypropylamino)-acetamido]benzophenone could be dehydrated to give a mixture of the same two compounds by heating at reflux 72 hours in ethanol or by heating 65 hours at reflux in xylene.

Method B A solution of 5.4 g. (20 mmol) of 7-chloro-l ,3-dihydro-5-phenyl-2H-l,4-benzodiazepin-2-one and 20 mmol of stannic chloride in 300 ml. of dry benzene was treated with 60 mmol of propylene oxide and stirred under dry nitrogen for 22 hours at 80. The reaction mixture was concentrated in vacuo to a residue which was partitioned between methylene chloride and ammonia. The organic phase was washed with water, dried and concentrated to give a crystalline residue. Recrystallization from ethyl acetate gave colorless prisms,

19 m.p. l78l83, of a mixture of the above-titled compounds.

Similarly, this reaction was effected in benzene solution using aluminum trichloride, titanium tetrachloride or boron trifluoride etherate as catalysts.

Method C Following the procedures set forth in Examples 12 and 13, the mixtures obtained in Methods A and B can be separated in order to isolate lO-chloro-2,3,5,l lbtetrahydro-Z-methyl-l l b-phenyloxazolo[ 3,2- d][l,4]benzodiazepin-6(7H)-one (2,] lb cis) and 10- chloro-2,3 ,5,1 lb-tetrahydro-Z-methyl-l lb-phenyloxazolo-[3,2-d][1,4]benzodiazepin-6(7H)-one (2,1 lb trans).

EXAMPLE 1 5 Preparation of l-chloro-2,3,5,l lb-tetrahydro-3-methyl-l 1bphenyloxazolo[ 3,2-d][ l,4]benzodiazepin-6(7H)-one (3,1 lb cis) A mixture of 79.4 g. (225 mmole) of 2-(2- bromoacetamido)-5-chlorobenzophenone, 25 g. of 2- aminopropanol hydrochloride, 95 ml. of triethylamine and 500 ml. of ethanol was stirred overnight at room temperature, and then at reflux for 5 hours. The solu- ,tion was concentrated under reduced pressure to a residue which was partitioned between ether and water. The organic layer was washed with water, dried and treated with hydrogen chloride to give 18 g. of a colorless solid. Recrystallizations from ethanol-ether gave prisms of 5-chloro-2-[2-( l-hydroxy-2- propylamino)acetimido]-benzophenone, hydrochloride, m.p. l83186.

A solution of 5 g. (13 mmol) of the free base 5- chloro-2[ l-hydroxy-2-propylamino)acetamido]benzophenone was heated 16 hours in refluxing pyridine (100 ml.). The solution was concentrated in vacuo to an oil which was chromatographed over silica. The first material taken in 60% ethyl acetate, 40% hexane was 2-amino-5-chlorobenzophenone. The next material eluted was combined to give lQ-chloro-2,3,5,1 lb-tetrahydro-3-methyl-l lb-phenyloxazolo[ 3,2-d][ 1,4]benzodiazepin-6(7H)-one (3,1 lb cis) which was recrystallized 3 times to give colorless prisms, m.p. 8896. Sublimation under reduced pressure gave a colorless solid, m.p. 8498.

EXAMPLE 16 Preparation of lO-chloro-l lb-(2-chlorophenyl)-2,3,5,l lb-tetrahydrooxazolo[3,2-d] [l,4]benzodiazepin-6(7H)-one -dihydro- A suspension of 4.3 g. (0.0328 M) of aluminum chloride in 200 ml. of dry benzene under nitrogen was treated with 5.0 g. (0.0164 M) of 7-chloro-5-( 2-chlorophenyl l ,3-dihydro-2H-l ,4-benzodiazepin-2-one and the mixture wa stirred in an ice bath for 20 min. when 2.2 g. (0.0492 M) of ethylene oxide was added and after I 8 hr. at room temperature, an additional 2.2 g. of ethylene oxide was added. After 3 hr., the mixture was heated under reflux for 10 min., then evaporated to dryness.

The residue was made basic with ammonium hydroxide, dichloromethane 100 ml.) was added and the mixture was filtered. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether and recrystallized from a mixture of dichloromethane and petroleum ether to give lO-chloro-l 1b-( 2-chlorophenyl )-2,3 ,5 ,l lb-tetrahydrooxazolo[ 3,2-d] l ,4] benzodiazepin- 6(7H)-one as white prisms, m.p. 2l3-2l6.

EXAMPLE 1 7 Preparation of l O-chloro-l lb-( 2-chlorophenyl )-7-methoxymethyl- 2,3,5 ,1 1b-tetrahydrooxazolo[ 3 ,2-d] l,4]benzodiazepin-6(7l-l)-one A solution of 2.8 g. of IO-chloro-l lb-(2-chlorophenyl)-2,3,5,l lb-tetrahydrooxazolo[3,2-d] l ,4]benzodiazepin-6(7H)-one in 50 ml. of dimethylformamide was cooled to -l0 and treated with 0.65 g. of sodium methoxide. After stirring for 5 minutes, the mixture was cooled to 40 and 1 ml. of chlorodimethyl ether was added. The cooling bath was removed and when the temperature had reached 0 the reaction mixture was poured into 300 ml. of ice-water. The precipitated material was collected by suction and dissolved in methylene chloride. The solution was dried over sodium sulfate, filtered and evaporated. The residue was crystallized from a mixture of ether and hexane to give, after recrystallization from ethanol, lO-chloro-l lb-(2- chlorophenyl)-7-methoxymethyl-2,3,5,l lb-tetrahydrooxazolo[3,2-d] [l,4]benzodiazepin-6(7H)-one as white prisms, m.p. l44-l47.

EXAMPLE 1 8 Preparation of Ethyl 7-chlorol ,3-dihydro-5phenyl-2H-l ,4-benzodiazepin- 2-one-3-carboxylate A solution of 50 g. of sodium nitrite is added dropwise to a solution of 34.6 g. of ethyl 2-benzoyl-4- chloro-malonanilate in 250 ml. of glacial acetic acid. After 1 /2 hours stirring at room temperature, the oxime crystallizes out and is filtered off by suction, washed with water and dried in vacuum. Ethyl 2-benzoyl4chloro-mesoxalanilate 2-oxime, m.p. 98l05 is obtained.

Water is added dropwise to the filtrate with stirring whereby further oxime crystallizes out.

According to thin layer chromatogram, the crude product consists of a mixture of the two stereoisomeric oximes. These may be separated by chromatography on Kieselgel with 20% acetic ester in methylene chloride. The first eluted isomer melts at l l5-l 17 after crystallization from alcohol-water. The oxime eluted later shows a m.p. of l3ll32 after crystallization from ether-hexane.

A solution of 2 g. of ethyl 2'-benzoyl-4'-chloromesoxalanilate 2-oxime in 40 ml. of methylene chloride is treated with 2 g. of Zinc dust. 4 ml. of glacial acetic acid are added dropwise within 5 minutes with stirring.

After the addition, the mixture is stirred at room tem I perature for l hour. The reaction mixture is filtered and the filtrate evaporated. The residue is boiled under reflux for 2 hours in 20 ml. of benzene and 2 ml. of glacial acetic acid. The reaction mixture is washed out with 10% soda solution, dried over sodium sulphate and evaporated. Crystallization of the residue from alcohol yields ethyl 7-chloro-l,3-dihydro-5-phenyl-2H- l ,4-benzodiazepin-2-one-3-carboxylate, m.p. 232234. Further material crystallizes from the mother liquor.

EXAMPLE 19 Preparation of 10-chloro-1 1b-pheny1-2,3,5, l 1 b-tetrahydrooxazolo [3,2-d] l ,4]benzodiazepin-6(7H)-one-5-carboxylic acid ethyl ester To a solution of 3.1 g. (0.01 18 M) of stannic chloride in 35 ml. of dry ethylene dichloride under nitrogen was added 1.5 g. (0.00438 M) of 7-chloro-l ,3-dihydro-2- oxo-5-phenyl-2H-l ,4-benzodiazepine-3-carboxylic acid ethyl ester. The reaction was stirred in an ice bath, when a solution of 1.0 g. (0.0233 M) of ethylene oxide in 5 ml. of ethylene dichloride was added. The mixture was stirred at room temperature for 3 hr. and then made basic with mixture of ammonium hydroxide and ice. The mixture was filtered, and the filtrate was dried with anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether. Recrystallization from a mixture of dichloromethane and petroleum ether gave l-chloro-l lb-phenyl-2,3,5,l lbtetrahydrooxazolo[3,2-d] 1,4]benzodiazepin- 6(7H)-one-5-carboxylic acid ethyl ester as white rods, m.p. 205207.

EXAMPLE 20 Preparation of l0-Chloro-l 1b-( 2-fluorophenyl)-7-(2-hydroxyethyl)- 2,3,5,1 1b-tetrahydr0oxazolo[ 3,2-d][ 1,4]benzodiaze- Method A A solution of 3.3 g (0.01 M) of 7-chloro-1-(2- hydroxyethyl) 2 fluorophenyl )-l ,3-dihydro-2H- l ,4- benzodiazepin-2-one in 40 ml of 1,2-dich1oro ethane under nitrogen was treated with 5.2 g (0.02 M) of stannic chloride with stirring. After min, the mixture was cooled in an ice bath and 2.6 g (0.06 M) of ethylene oxide was added. After 1 hr at room temperature, the reaction mixture was made basic with ammonium hy droxide and filtered. The precipitate was washed with dichloromethane, and the combined filtrates were separated. The organic layer was washed with 40 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of ether and petroleum ether and recrystallized from toluene to give the above named product as white prisms, mp l42l47.

Method B A solution of 5 g (0.015 M) of l0-chloro-l1b-(2- fluorophenyl )-2,3,5,l lb-tetrahydrooxazolo[3 ,2- d][1,4]benz0diazepin-6(7H)-one in 50 ml of dry N,N- dimethylformamide under nitrogen was treated with 1.3 g (0.030 M) of a 57% dispersion of sodium hydride in mineral oil and after 30 min, 4.0 g (0.030 M) of 2- bromoethanol was added. The mixture was kept at 60 for 18 hrs, when 450 ml of water was added, followed by enough 3N hydrochloric acid to lower pH to less than 5. The mixture was extracted with dichloromethane (3 X 125 ml). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and evporated to dryness. The residue was dissolved in ether (50 ml) and filtered through 75 g of neutral alumina. Elution with ethyl acetate and methanol gave the above named product, which was crystallized from ether to give the product as white prisms, mp 142147.

EXAMPLE 21 Preparation of 1 lb-( 2-Fluoropheny1 )-2,3 ,5-1 lb-tetrahydro- 1 O-iodooxazolo[ 3,2-d][ 1,4]benzodiazepin-6( 7H )-one To a mixture of 5.34 g (40 mmole) of aluminum chloride and 250 m1 of benzene was added 7.6 g (20 mmole) of 5-(2-fluorophenyl).-1 ,3-dihydro-7-iodo-2l-l- 1,4-benzodiazepin-2-one. This mixture was then cooled in an ice bath, 10 ml (0.2 mole) of ethylene oxide was added to it and then it was stirred for 2 days at room temperature. The mixture was concentrated in vacuo and the residue shaken with methylene chloride and saturated sodium bicarbonate solution. The insoluble material was filtered off and discarded. The methylene chloride layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized with ether to give the above named product, mp 180184. Recrystallization from aqueous ethanol gave colorless needles, mp 193196.

EXAMPLE 22 Preparation of l 1b-(2-Fluorophenyl)-7-(2-hydroxyethyl)-10- iodo2,3,5,l lb-tetrahydrooxazolo[3,2-d][ l ,4]benzodiazepin-6( 7H )-one A solution of 0.8 g (0.00187 M) of 11b-(2fluorophenyl )-2,3 ,5-1 lb-tetrahydro-10-iodo-oxazolo[3,2- d][1,4]benzodiazepin-6(7l-l)-one in 25 ml of dry N,N- dimethylformamide under nitrogen was treated with 0.1 1 g (0.00262 M) of a 57% dispersion ,of sodium hydride in mineral oil. After stirring for 30 minutes in an ice bath, 0.37 g (0.00374 M) of 2-bromoethanol was added, and the reaction was heated to l 15120 for 3 hr and at 130 for 1 hr. The solvent was removed under vacuum, and the residue was dissolved in 25 ml of dichloromethane and washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was heated under reflux for 15 minutes in a solution of 10 m1 of triethylamine, containing 0.5 g (0.005 M) of succinic anhydride. Solvent was removed under reduced pressure and the residue was dissolved in 25 ml of dichloromethane. The half ester was extracted into 20 ml of dilute ammonium hydroxide which was then treated with 5 ml of 3N sodium hydroxide for 1 hr. Thesolution was extracted with 25 ml of dichloromethane, which was dried with anhydrous sodium sulfate, and'evaporated. The resulting oil was crystallized from ether to give the above named product as white plates, rnp 165.

EXAMPLE 23 Preparation of 1 1b-( 2Chlorophenyl)- l 0-nitro-2,3,5 ,l 1 b-tetrahydrooxazolo[ 3,2-d][ l ,4]-benzodiazepin-6(7l-l)-one A solution of 5.2 g (0.02 M) of stannic chloride in 60 ml of dry ethylene dichloride under nitrogen was treated with 2.9 g (0.0091 M) of 5-(2-chlorophenyl)- 1,3-dihydro-7-nitro-2l-l- 1 ,4-benzodia2epin-2-one. The reaction was cooled in an ice bath, and 2.6 g (0.06 M) of ethylene oxide in 10 ml of ethylene dichloride was added with stirring over an 8 min period. After 18 hr at room temperature, the solution was made basic with concentrated ammonium hydroxide and filtered. The filtrates were washed with a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to 23 dryness. The residue was crystallized from a mixture of dichloromethane, methanol and petroleum ether to give the above named product as white rods, melting at 201203.

EXAMPLE 24 Preparation of l 1b-(2Chlorophenyl)-7-(2-hydroxyethyl)-10- nitro2,3 ,5 ,1 lb-tetrahydrooxazolo[ 3,2-d][ 1 ,4]benzodiazepin-6(7H)-one A solution of 1.5 g (0.0041 M) of llb-(2-chlorophenyl 1 -nitro-2,3 ,5 ,1 lb-tetrahydrooxazolo 3 ,2-

d][ l ,4]benzodiazepin-6(7H)-one in 30 ml of dry N,N- dimethylformamide was treated with 0.34 g (0.008 M) of a 57% dispersion of sodium hydride in mineral oil with stirring under nitrogen. After 30 min, 1.5 g (0.012 M) of 2-bromoethanol was added and the reaction was heated to 90 for 3 hr. The solvent was removed under vacuum, and the residue was dissolved in 50 ml of dichloromethane which was then washed with 50 ml of water, 25 ml of a saturated solution of brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether, and recrystallized from a mixture of dichloromethane and methanol to give the product as pale yellow prisms, m.p. l85l90(dec.).

EXAMPLE 25 In an analogous manner to the procedures described in Example 24, the following compounds may be prepared using lO-chloro-l 1b-(2-fluorophenyl)- 2,3 ,5,1 lb-tetrahydrooxazolo[3,2-d][ 1,4]benzodiazepin-6(7H )-one as the starting material:

thylaminoethyl)-2,3 ,5 ,1 lb-tetrahydrooxazolo[ 3 ,2- d][ l ,4]benzodiazepin-6('7H) one, from (2-bromo ethyl)dimethylamine -Chloro-l lb-( 2-fluorophenyl )-7-( 3-aminopropyl 2,3,5,l lb-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6 (7H)one, from 3-bromopropylamine l0-Chloro-1 lb( 2-fluor0phenyl)-7-( 3methylaminopropyl )-2,3,5,1 lb-tetrahydrooxazolo[3,2-

d][ l ,4]benzodiazepin-6(7H)one, from (3-bromopropyl)methylamine lO-Chloro-l lb-( 2-fluorophenyl )-7-( Z-diethylaminoethyl)-2,3,5 ,1 lb-tetrahydro0xazolo[3,2- d][ l ,4]benzodiazepin-6(7H)-one, from (2bromoethyl)diethylamine EXAMPLE 26 Preparation of 10 -Chloro-1 1b-(2-fluorophenyl )-7-(2-hydroxyethyl 2,3,5,l lb-tetrahydrooxazolo[3,2-d] l ,4]benzodiazepin-6(7H)-one A solution of 33.3g (0.1 M) of l0-chloro-l1b-(2- fluorophenyl)-2,3,5,l lb-tetrahydrooxazolo[ 3 ,2-d] [l,4]benzodiazepin-6( 7H)-one in 100 ml of dry N,N- dimethylformamide was treated with 6.6g (0.138 M) of a 50 percent dispersion of sodium hydride in mineral oil. The mixture was stirred for 0.5 hour at room temperature, was then cooled to 5l0 and treated with a solution of 3 lg (0.186 M) of ethyl bromoacetate in 25 ml of dry N,N-dimethylformamide. The resulting mixture was allowed to stir at room temperature for 18 hours when 3 ml of water was carefully added. The solution was next evaporated to dryness under reduced pressure. The residue was next treated with 50 ml of toluene and evaporated to dryness. This procedure was repeated twice in order to azeotrope any remaining water or N,N-dimethylformamide. The crude ester thus obtained was dissolved in 250 ml of dry tetrahydrofuran, cooled to 0 and was treated by the portionwise addition of 1.9g (0.05 M) of lithium aluminium hydride. The cooling bath was removed and the mixture was allowed to stir for 3 hours. Enough saturated sodium bicarbonate solution was added to coagulate the solids and the mixture was filtered. The filtrates were concentrated to dryness and dissolved in dichloromethane. The solution was washed with lN hydrochloric acid, water, saturated brine, dried over anhydrous sodium sulfate and evaporated. The residue was crystallized from toluene to give the above named product as white prisms, m.p. l42147.

EXAMPLE 27 Preparation of 5Chloro-2-fluoro-2-( 2-hydroxyethyl )aminobenzophenone A solution of 10g (0.04 M) of 2-amino-5-chloro-2- fluorobenzophenone in 100 ml of dry benzene was treated with 10.6g (0.08 M) of aluminum chloride under nitrogen. The reaction mixture was next treated with 7g (0.16 M) of ethylene oxide (5 minute period), keeping the temperature below 35 with an ice bath. After 65 hours at room temperature, the procedure was repeated using the same amounts of aluminum chloride and ethylene oxide as before. After 5 hours at room temperature, the benzene was removed by distillation, and the residue was made basic with ammonium hydroxide, stirred with 100 ml of dichloromethane and filtered. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The product was recrystallized three times from a mixture of ether and petroleum ether to give the above named product as yellow needles, m.p. 96-10l.

EXAMPLE 28 Preparation of 2-(2-Acetoxyethylamino)-5chloro-2 fluorobenzophenone A solution of 15g (0.0516 M) of 5-chloro-2-fluoro-2- (2-hydroxyethyl)amino-benzophenone in ml of acetic anhydride was heated on the steam bath for 1 hour. Solvent was removed under reduced pressure and the residue was dissolved in 75 ml of benzene. This solution was filtered through a column of 100g of silica gel. The column was eluted with 500 ml of benzene which was discarded, and l l. of dichloromethane. Removal of the dichloromethane gave a residue which was crystallized from a mixture of ehter and petroleum ether to give the above named product as yellow rods, m.p. 4855.

EXAMPLE 29 Preparation of 2-[N-( 2-Acetoxyethyl )-N-( 2-bromoacetyl)amino]-5- chloro-2fluorobenzophenone A mixture of 2.5g (0.0074 M) of 2-(2-acetoxyethylamino)-5-chloro-2-flu0robenzophenone and 5g (0.0362 M) of potassium carbonate in25 ml of dry chloroform was treated with 2.0g (0.0096 M) of bromoacetyl bromide over a 20 minute period with stirring. The mixture was stirred for 1 hour at room temperature when 25 ml of water was added, and the chloroform layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was dissolved in ml of benzene, and chromatographed over 100g of Florisil. Elution with l l. of benzene gave 0.2g of an oil and elution with 1.5 l. of ether and 1 l. of ethyl acetate gave 1.8g and 1.0g, respectively of a colorless oil which were combined and recrystallized from a mixture of dichloromethane and petroleum ether to give the above named product as white prisms, m.p. 84-88.

EXAMPLE 30 Preparation of 7-( 2-Acetoxyethyl 1 O-chloro-l lb-( 2-fluorophenyl 2 ,3,5 ,l lb-tetrahydrooxazolo 3 ,2-d] l ,4]benzodiazepin-6( 7H )-one A solution containing 1.5g (0.0033 M) of 2-[N-(2- acetoxyethyl)-N-(2-bromoacetyl)amino]-5-chloro-2 fluorobenzophenone, 0.5 ml of triethylamine and 0.23g (0.0036 M) of ethanolamine in ml of benzene was kept at room temperature for 65 hours and then was partitioned between 25 ml of ethyl acetate and 25ml of water. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was partioned between ml of ether and 20 ml of 1N hydrochloric acid. The acid layer was separated and extracted with ml of ethyl acetate. The organic layer was then washed with 20 ml of dilute ammonium hydroxide, dried over anhydrous sodium sulfate and evaporated to dryness. The residual oil was crystallized from ether and recrystallized from a mixture of methanol and water to give the above named product as white prisms, n'Lp. 120 123.

EXAMPLE 31 Preparation of 10-Chloro-1 lb-( 2-fluorophenyl)-7( 2-hydroxyethyl)-2,3,5,l 1b-tetrahy drooxazolo[3,2-d] l,4]benzodiazepin-6(7H)-onc A solution of 0.5g (0.0012 M) of 7-(2-acetoxyethyl) l0chloro-l lb-( 2-fluorophenyl )-2,3,5,1 lb-tetrahydrooxazolo[3,2-d] [1,4]benzodiazepin-6(7H)-one in 5 ml of methanol was treated with 2 ml of 3N sodium hydroxide. After 3 hours, 50 ml of water was added and the solution was extracted with 40 ml of dichloromethane, which was then dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from a mixture of methanol and water to give l0-chloro-l lb-( 2'fluorophenyl )-7-( 2-hydroxyethyl) 2,3,5,l lbtetrahydrooxazolo(3,2-d) 1,4]benzodiazepin-6(7H)-one as white prisms, m.p. and m.m.p. l4l-l46.

EXAMPLE 32 The pharmacological activity of a series of compounds of the present invention was determined in standard screening tests. Compounds which were employed in these experiments were as follows:

lO-chloro-7-( Z-hydroxyethyl )-2,3,5,l lb-tetrahydrol lb-phenyloxazolo[ 3,2-d] 1,4]benzodiazepin-6- (7H)-one (COMPOUND A) l0-chloro-l 1b-( 2-fluorophenyl )-7-( 2-hydroxyethyl 2,3,5,1 lb-tetrahydrooxazolo[3,2-d] 1,4]benzodiazepin-6-(7H )-one (COMPOUND B) l0-chloro-l 1b-( 2-fluorophenyl)-2,3,5 ,l lb-tetrahydrooxazolo[3,2 -d], [l ,4]benzodiazepin-6-(7H)-one (COMPOUNDC) lO-chloro-2,3 ,5,1 1 b-tetrahydro- 1 1 b-phenyloxazolo- [3,2-d] 1 ,4]benzodiazepin-6-( 7l-l)-one (COM- POUND D) l0-chloro-7-methyl-2,3 ,5 ,l lb-tetrahydro-l 1bphenyloxazolo[ 3,2-d] l ,4]benzodiazepin-6-(7H )-one (COMPOUND E) 10-chloro-2,7-dimethyl-2,3 ,5 ,l lb-tetrahydro-l 1 bphenyloxazolo[3,2-d] [l,4]benzodiazepin-6-(7H)-one (COMPOUND F) 10-chloro-2chloromethyl-2,3,5 ,1 lb-tetrahydro-7- methyl-1 1b-phenyloxazolo[3,2-d] l ,4]benzodiazepin 6-(7l-l)-one (COMPOUND G) l0-Chloro-7-methyl-2,3,5,6,7,1 lb-hexahydro-l lbphenyloxazolo[3,2-d] [l,4]benzodiazepine (COM- POUND H) The tests employed in this experiment were the following:

Foot Shock This test is a screen for compounds having muscle relaxant and/or anti-anxiety (tranquilizer) activity. A pair of mice is confined under a one liter beaker placed on a grid which presents shock to the feet. At least 5 fighting episodes are elicited in a 2-minute period. Pairs of mice are marked and pretreated by oral dosage 1 hour prior to a second shocking. Logarithmic-dose intervals are utilized up to a maximum of mg/kgm. At the 100 percent blocking dose, 3 out of 3 pairs must be blocked from fighting.

Inclined Screen The test is useful in determining muscle relaxant and- /or sedative activity. Groups of 6 male mice are given the test drug (maximum dose of 500 mg/kg) and then are left on the inclined screen at least four hours for observation of paralyzing effects severe enough to cause them to slide off the screen. If activity is observed, additional doses are tested until at least two are reached at which some, but not all the animals slide off the screen. Doses at which mice fall off the screen due to toxicity or excitation are not included in the calculation of PD The PD is determined from a graph on which dose is plotted against percent of mice paralyzed. This PD value is defined as the dose in mg/kg which can be expected to cause 50 percent of mice to slide off the screen.

Unanesthetized Cat Cats are treated orally and observed for minimum symptoms usually ataxia. One cat is used at a dose of 50 mgm/kgm. If activity is present, up to three cats/dose are used. Results are given as minimum effective dose. This test is useful in determining muscle relaxant activ- 1ty.

Antimetrazol This test determines anticonvulsant and/or sedative activity of compounds in mice. The test compound is administered orally to groups of four mice at various dose levels. One hour later, metrazol (at a dose level previously determined to be sufficient to induce convulsive seizures in all test animals -l25 mg/kg) is administered subcutaneously and the animals are observed for protection from convulsive seizures. Results are recorded as the number of animals protected 27 against convulsions. The dose at which 50 percent of the animals are protected from convulsive seizures is expressed as the ED The test results from the above tests using indicated compounds of the present invention are summarized below in Table I.

28 2. The mixture was further blended by passing through a Fitzpatrick Comminuting Machine with a number 1A screen with knives forward.

3. The blended powder was returned to the mixer, the tale added and blended thoroughly.

4. The mixture was filled into number 4 hard shell TABLE I Footshock Compound 100% Blocking Inclined Screen Unanesthetized Antimetrazole Dose Level PD Cat MED ED Compound A 20 mg. 50 mg. 5 mg. Compound B 4 mg. mg. 5 mg. 2.034 mg. Compound C 1 mg. 8 mg. Compound D 10 mg. mg. Compound E 100 mg. 300 mg. Compound F 80 mg. 250 mg. Compound G 100 mg. 300 mg. 10 mg. 24 mg. Compound H 500 mg.

gelatin capsules on a Parke Davis capsulating machine. (An similar t e ca sulatin machine ma be used.) EXAMPLE 33 y yp p g y COMPOUND C (IO-chloro-l1b-(2-fluorophenyl)- 2,3 ,5,1 lb-tetrahydrooxazolo[ 3,2-d] 1 ,4]benzodiazepin-6(7I-I)-one) was prepared in the form of several pharmacological formulations as follows:

A. Suppository Formulation E. F. Drew Company 522 Fifth Avenue New York, New York 35 E. F. Drew Company 522 Fifth Avenue New York, New York Procedure:

1. The Wecobee M and the carnauba wax were melted in a suitable size glass-lined container (stainless steel may also be used), mixed well and cooled to 45C.

2. The IO-chloro-l 1b-(2-fluorophenyl-2,3,5,1lb-tetrahydrooxazolo [3,2-d] 1,4]benzodiazepin- 6(7I-I)-one which had been reduced to a fine powder with no lumps, was added and stirred until completely and uniformly dispersed.

3. The mixture was poured into suppository molds to yield suppositories having an individual weight of 1.3 Grams.

4. The suppositories were cooled and removed from molds. They were then individually wrapped in wax paper for packaging (foil may also be used).

B. Capsule Formulation Per Capsule 1. lO-Chloro-l lb-(2-fluorophenyl -2,3,5.1 lb-tetrahydrooxazolo [3,2-d] 1,4]benzodiazepin- 6(7H)-one, lactose and corn starch were mixed in a suitable mixer.

C. Parenteral Formulation Procedure (For 10,000 cc):

1. The 50 Grams of 10-chloro-l lb-(2-fluorophenyl)- 2,3,5,1 1b-tetrahydrooxazolo[3,2-d][ 1,4]benzodiazepin-6(7I-I)-one were dissolved in cc of benzyl alcohol; 4,000 cc of propylene glycol and 1,000 cc of ethanol were added.

2. The 12 Grams of benzoic acid were dissolved in the above. The 48.8 Grams of sodium benzoate dissolved in 3,000 cc of Water for Injection were added. The solution was brought up to final volume of 10,000 cc with Water for Injection.

3. The solution was filtered through an 02 Selas candle, filled into suitable size ampuls, gassed with N and sealed. It was then autoclaved at 10 psi for 30 minutes.

D. Tablet Formulation Per Tablet IO-Chloro-l lb-(2-fluorophenyl )-2,3.5,1 1btelra-hydrooxazolol 3,2-d 1,4]bcnzo- 25.00 Mg. diazepin-6( 7H )-one Dicalcium Phosphate Dihydrate. Unmilled 175.00 Mg. Corn Starch 24.00 Mg. Magnesium Stcaratc 1.00 Mg. Total Weight 225.00 Mg.

EXAMPLE 34 The formulations of Example 33 were repeated using COMPOUND B [IO-chloro-l lb-(2-fluorophenyl )-7- (2-hydroxyethyl )-2,3 ,4,1 lb-tetrahydrooxazolo[ 3,2-

EXAMPLE 35 H \CH2 )n wherein A is selected from the group consisting of CH and Z is a hetero atom selected from the group consisting of -O and where R is hydrogen, lower alkyl or lower alkanoyl containing from 2-7 carbon atoms; n is an integer from I to 2; R is hydrogen, nitro, trifluoromethyl, halogen, lower alkyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, cycloalkyl-lowcr alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower alkylamino-lowcr alkyl, or di-lower alkylaminodower alkyl; R is hydrogen, lower alkyl or the group -COO lower alkyl; R is hydrogen, lower alkyl and -CHl ,X where X is selected from the group consisting of chlorine, bromine, lower alkoxy, lower alkoxy-lower alkyl and di-lower alkyl-amino; and R is hydrogen, lower ulkyl, pyridyl, phenyl and phenyl substituted with a member selected from the group consisting of halogen, nitro, trifluoromethyl and lower alkyl.

2. A compound of the formula L R )n wherein Z is a hetero atom selected from the group consisting of O and where R is hydrogen, lower alkyl or lower alkanoyl containing from 2-7 carbon atoms; n is an integer from 1 to 2; R is hydrogen, nitro, trifluoromethyl, halogen, lower alkyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, cycloalkyl-lower alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl; R is hydrogen, lower alkyl or the group -COO- lower alkyl; R, is hydrogen, lower alkyl and -CH X where X is selected from the group consisting of chlorine, bromine, lower alkoxy, lower alkoxy-lower alkyl and di-lower alkylamino; and R is hydrogen, lower alkyl, pyridyl, phenyl and phenyl substituted with a member selected from the group consisting of halogen, nitro, trifluoromethyl and lower alkyl.

3. A compound of claim 2 wherein R is chlorine joined to the 7-position of the benzodiazepine ring, R is methyl, R and R are hydrogen, R is phenyl, Z is O-, and n is 1, i.e., l0-chloro-7-methyl- 2,3,4,6,7,1 lb-hexahydro-l lb-phenyloxazolo[ 3,2- d][ 1,4]benzodiazepine.

4. The compound of claim 2 wherein Z is O-, R is chlorine joined to the 7-position of the benzodiazepine ring, R is methyl, R and R are hydrogen, R is phenyl and n is 2, i.e., l l-chloro-3,4,6,7,8,12b-hexahydro-8-methyl- 1 2b-phenyl-2H-[ 1 ,3]-oxazino[3,2-

d][ l ,4]benzodia7epine.

5. A compound of the formula wherein A is selected from the group consisting of CH4 and where R,- is hydrogen, lower alkyl or lower alkanoyl containing from 27 carbon atoms; n is an integer from l to 2; R, is hydrogen, nitro, trifluoromethyl, halogen, lower alkyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, cycloalkyl-lower alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkyl-amino-lower alkyl; R, is hydrogen, lower alkyl or the group --COO lower alkyl; R, is hydrogen, lower alkyl and CH X where X is selected from the group consisting of chlorine, bromine, lower alkoxy, lower alkoxy-lower alkyl and di-lower alkylamino; and R is hydrogen, lower alkyl, pyridyl, phenyl and phenyl substituted with a member selected from the group consisting of halogen, nitro, trifluoromethyl and lower alkyl.

6. The compound of claim 5 wherein R, is chlorine joined to the 7-position of the benzodiazepine ring, R is methyl, A is 1 wherein A is selected from the group consisting of -CH and R, is hydrogen, halogen, nitro, trifluoromethyl, lower alkyl, lower alkyl mercapto or lower alkoxy, R is hydrogen, lower alkyl cycloalkyl-lower alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alkyl; R is hydrogen, lower alkyl or the group -COO lower alkyl; R, is hydrogen, lower alkyl and CH X where X is selected from the group consisting of chlorine, bromine, lower alkoxy, lower alkoXy-lower alkyl and di-lower alkylamino; and R is hydrogen, lower alkyl, pyridyl, phenyl and phenyl substituted with a mem ber selected from the group consisting of halogen, nitro, trifluoromethyl and lower alkyl.

9. A compound of claim 8 wherein R, is halogen and is joined to the 7-position of the benzodiazepine ring and A is 10. The compound of claim 9 wherein R, is chlorine, R R and R are hydrogen and R is phenyl, i.e., 10- chloro-2,3,5,l lb-tetrahydro-l lb-phenyloxazolo[ 3,2-

l 1. The compound of claim 9 wherein R, is chlorine, R is B-hydroxy ethyl, R and R are hydrogen and R is phenyl, i.e., lO-chloro-7-(2-hydroxyethyl)-2,3,5,l lbtetrahydro-l lb-phenyloxazolo- 3 ,2-d][ l ,4-]-benzodiazepin-6-(7H)-one 12. The compound of claim 11 wherein R, is chlorine, R and R are hydrogen, R is methyl and is joined to the 3-position of the heterocyclic ring, R is phenyl, i.e., lO-chloro2,3,5,l lb-tetrahydro-3-methyl-l lbphenyloxazolo[3 ,2-d][ l,4]-benzodiazepin-6- (7H)-one.

13. A compound of claim 8 wherein R, is halogen and is joined to the 7-position of the benzodiazepine ring, A is and R is o-halophenyl.

14. The compound of claim 13 wherein R, is chlorine, R R and R are hydrogen and R is o-fluorophenyl, i.e., l0-chloro-l lb-(2-fluorophenyl)-2,3,5,l lb-tetrahydrooxa2olo[ 3,2-d][ 1,41-benzodiazepin-6- (7H)-one.

15. The compound of claim 13 wherein R, is chlorine, R is B-hydroxy ethyl, R and R are hydrogen and R is o-fluorophenyl, i.e., lO-chloro-l lb-(2-fluorophenyl )-7-( Z-hydroxyethyl )-2,3,5, l lb-tetrahydrooxazolo[3,2-d][ l ,4]benzodiazepin-6-(7l-l )-one.

16. The compound of claim 8 wherein R, is halogen and is joined to the 7-position of the benzodiazepine ring, R is lower alkyl and A is 17. The compound of claim 16 wherein R, is chlorine, R is methyl, R and R are hydrogen and R is phenyl, i.e., lO-chloro-7-methyl-2,3,5,l lb-tetrahydrol lb-phenyloxazolo[3 ,2-d][ l,4]benzodiazepin-6- (7H)-one.

18. The compound of claim 16 wherein R, is chlorine, R is methyl, R is hydrogen, R, is chloromethyl and is joined to the 2-position of the heterocyclic ring and R is phenyl, i.e., lO-chloro-Z-chloromethyl- 2,3,5,l l b-tetrahydro-7-methyll lb-phenyloxazolo[3,2-d][ l ,4]benzodiazepin-6-(7H)-one.

19. The compound ofclaim 16 wherein R, is chlorine, R is methyl, R is hydrogen, R, is methyl joined to the 2-position of the heterocyclic ring and R is phenyl.

20. l()-Chloro-2methyl-2,3,5,l lbtetrahydro-l lbphenyloxazolo[ 3,2-d l ,4]benzodiazepin-6( 7H )-one (2,1lbcis).

21. l0-Chloro-2-methyl-2,3,5,l lbtetrahydro-l lbphenyloxazolo[ 3 ,2-d][ 1 ,4]benzodiazepin-6( 7H )-one (2,1lb trans).

33 22. A process for the preparation of a compound of the formula A H R N R R wherein A is selected from the group consisting of -CH and R is hydrogen, halogen, nitro, trifluoromethyl, lower alkyl, lower alkyl mercapto or lower alkoxy; R is hydrogen, lower alkyl, cycloalkyl-lower alkyl, hydroxylower alkyl, amino-lower alkyl, mono-lower alkylamino-lower alkyl, or di-lower alkylamino-lower alwherein R R R R and A are as described above with an epoxide compound of the formula wherein R is as described above in the presence of an UNITED STATES PATENT OFFICE page 1 of 2 CERTIFICATE OF CORRECTION Patent No. 3,905.956 Dated September 16. 1975 Inventor) Michael Edward Derieg, et a1 It ie certified that error appears in the above-identified patent and that said' Letters Patent are hereby corrected as shown below:

Columns 31 and 32 as shown on the attached sheet should be added, but will apply to Grant only; Signed and Scaled this Thirty-first Day of August 1976 Arrest:

RUTH c. MASON c. MARSHALL DANN Arresting Officer Commissioner uflarenrs and Trademarks I to 2; R. is hydrogen. nitro. trifluoromethyl. halogen. lower alkyl. lower alkyl mercapto or lower alkoxy; R is hydrogen. lower alkyl. cycloalkyl-lower zillt'yhhydroxylower alkyl. amino-lower alkyl. mono-lower alkylamino-lower alkyl. or di-lower alkyl-amino-lower alkyl; R, is hydrogen. lower alkyl or the group -COO lower alkyl; R. is hydrogen, lower alkyl and C H X where X is selected from the group consisting of chlorine. bromine, lower alkoxy. lower allgjoXy-lower alkyl and di-lower alkylamino; and R is hydrogen. lower alkyl. pyridyl. phenyl and phenyl substituted with a member selected from the group consisting of halogen. nitro. trifluoromethyl and lower alkyl.

6. The compound of claim wherein R. is chlorine joined to the 7-position of the benzodiazepine ring. R, is methyl. A is wherein A is selected from the group consisting'of CH and R is hydrogen. halogen. nitro. trilluoromethyl. lower alkyl. lower alkyl mercapto or lower alkoxy. R is hy-' drogcn. lower alkyl cycloalkyl-lower alkyl. hydroxylower alkyl. amino-lower alkyl. mono-lower alkylamino-lower alkyl. or di-lower alkylnmino-lower alkyl; R is hydrogen. lower alkyl or the group CO()- lower ulkyl; R. is hydrogen. lower alkyl and CH X where X is selected from the group consisting of chlorine. bromine. lower alkoxy. lower zllkoxy-lower alkyl and di-lowcr alkylamino; and R is hydrogen. lower alk \l. pyridyl. phenyl and phenyl substituted with a member selected from the group consisting of halogen. nitro. trifluoromethyl and lower alkyl.

9. A compound of claim 8 wherein R. is halogen and r is joined to the 7-position or the benzodiazepine ring and A is P 32 age Z of 2 10. The compound of claim 9 wherein R. is chlorine. R R and R. are hydrogen and R is phenyl. i.e.. l0- chloro-2'.3.5,l lb'tetrahydro-l l h-phenyloxazolo[ 3.2-

d l.4]-benzodiazepin-6-( 7H )-one.

H. The compound of claim 9 wherein R. is chlorine. R is ,B-hydroxy ethyl. R and R are hydrogen and R is phcnyl. i.e.. l0-chloro-7-(Z-hydroxyethyl)-2.3.5,l lbtetrahydro- I lb-phenyloxazolo-[ 3.2-d][ l .4-j-benzodia7epin-6-( 7H )-one. l

12. The compound of claim ll wherein R. is chlorine. R and R are hydrogen. R. is methyl and is joined to the 3-position of the heterocyclic ring, R is phcnyl. i.e.. lO-chloro-2.3,5.l lb-tetrahydro-3-methyl-l lbphenyloxazolo[3,2-d][ l.4l-benzodiazepin-6- 13. A compound of claim 8 wherein R. is halogen and is joined to the 7-position of the hemodiazepine ring. A is and R is o-halophenyl.

[4. The compound of claim l3 wherein R, is chlorine. R R and R. are hydrogen and R is o-l'luorophenyl. i.e.. lll-chloro-l lh-(Z-fluorophenyl)-2.3.5.l lh-tetrahydrooita zold 3,2-d][ l .4 l-benzodi'azepin-o- (7H)-one.

IS. The compound of claim l3 wherein R. is chlorine. R is B-hydroxy ethyl. R and R. are hydrogen and R is o-fluorophenyl. i.e.. lU-chloro-l lh-(Lfluorw phenyl )-7-( Z-hydroxycthyl )-2.3.5 I lh-tett'ahydrtmxazolol 3.2-d 1| l .4 lhenzodiuzcpin-o-t 7H l-one.

16. The compound otcluim 8 herein R. is halogen and is joined to the 7-position of the henzodiuyepine ring. R; is lower alkyl and A is 17. The compound of claim 16 wherein R. is chlorine. R is methyl. R and R. are hydrogen and R is phenyl. i.e.. l(l-Chl0I'0-7-m8tl1)l-2.3.5.l lh-tetrahydrol lh-phenyloxuzolo[3.2-d l .4 lhenzodiazepin-- (7H)-one.

18. The compound of claim 16 wherein R. is chlorine. R is methyl. R. is hydrogen. R. is chloromethyl and is joined to the 2-position oi the heterocyclic ring and R,-. is phenyl. i.e.. lO-chloro-Z-chloromethyl- 2.3.5.l lh-tetruhydro-7-methyl-l lb-phenyloxuzolol 3.2-1! IA ]hcnzodiuzcpin-6-( 7H )-one.

I). The compound of claim l6 wherein R. is chlorinc: R- is methyl. [1,, is hydrogen. R. is methyljoined to the 2-position of the hcterocyclic ring and R, is phenyl.

20. lll-(hloro-Z-methyl-2.3.5.l lh-tctruhydro-l lbphenyloxazolol 3.2-d H l.4 lhenzodiazepin-ot 7H l-one (2.llhcis). v

2l.' lU-(hloro-2-methyl 2.3.5.l lh-tetrahydro-l lb- I I phenyloxuzolol3.2-d1l l.4]herlZOdiflZepin-6(7H); (2.l lb trans). v v 

1. A COMPOUND FORMULA
 2. A compound of the formula
 3. A compound of claim 2 wherein R1 is chlorine joined to the 7-position of the benzodiazepine ring, R2 is methyl, R3 and R4 are hydrogen, R5 is phenyl, Z is -O-, and n is 1, i.e., 10-chloro-7-methyl-2,3,4,6,7,11b-hexahydro-11b-phenyloxazolo(3,2-d)(1, 4)benzodiazepine.
 4. The compound of claim 2 wherein Z is -O-, R1 is chlorine joined to the 7-position of the benzodiazepine ring, R2 is methyl, R3 and R4 are hydrogen, R5 is phenyl and n is 2, i.e., 11-chloro-3,4,6,7,8,12b-hexahydro-8-methyl-12b-phenyl-2H-(1,3)-oxazino(3,2 -d)(1,4)benzodiazepine.
 5. A compound of the formula
 6. The compound of claim 5 wherein R1 is chlorine joined to the 7-position of the benzodiazepiNe ring, R2 is methyl, A is
 7. The compound of claim 5 wherein R1 is chlorine joined to the 7-position of the benzodiazepine ring, R2 is methyl, A is -CH2-, R3 and R4 are hydrogen, R5 is phenyl and n is 1, i.e., 10-chloro-2,3,5,6,7,11b-hexahydro-7-methyl-11b-phenyl1H-imidazo(1,2-d)(1, 4)benzodiazepine.
 8. A compound of the formula
 9. A compound of claim 8 wherein R1 is halogen and is joined to the 7-position of the benzodiazepine ring and A is
 10. The compound of claim 9 wherein R1 is chlorine, R2, R3 and R4 are hydrogen and R5 is phenyl, i.e., 10-chloro-2,3,5,11b-tetrahydro-11b-phenyloxazolo(3,2-d)(1,4)-benzodiazepin-6-(7H)-one.
 11. The compound of claim 9 wherein R1 is chlorine, R2 is Beta -hydroxy ethyl, R3 and R4 are hydrogen and R5 is phenyl, i.e., 10-chloro-7-(2-hydroxyethyl)-2,3,5,11b-tetrahydro-11b-phenyloxazolo-(3,2 -d)(1,4-)-benzodiazepin-6-(7H)-one.
 12. THE COMPOUND OF CLAIM 11 WHEREIN R1 IS CHLORINE, R2 AND R3 ARE HYDROGEN, R4 IS METHYL AND IS JOINED TO THE 3-POSITION OF THE HETEROCYCLIC RING, R5 IS PHENYL, I.E., 10-CHLORO2,3,5,1 1 B-TETRAHYDRO-3-METHYL-11B-PHENYLOXAZOLO 3,2D)( 1,4)-BENZODIAZEPIN-6-(7H)-ONE.
 13. A compound of claim 8 wherein R1 is halogen and is joined to the 7-position of the benzodiazepine ring, A is
 14. The compound of claim 13 wherein R1 is chlorine, R2, R3, and R4 are hydrogen and R5 is o-fluorophenyl, i.e., 10-chloro-11b-(2-fluorophenyl)-2,3,5,11b-tetrahydrooxazolo(3,2-d)(1,4) -benzodiazepin-6-(7H)-one.
 15. The compound of claim 13 wherein R1 is chlorine, R2 is Beta -hydroxy ethyl, R3 and R4 are hydrogen and R5 is o-fluorophenyl, i.e., 10-chloro-11b-(2-fluorophenyl)-7-(2-hydroxyethyl)-2,3,5, 11b-tetrahydrooxazolo(3,2-d)(1,4)benzodiazepin-6-(7H)-one.
 16. The compound of claim 8 wherein R1 is halogen and is joined to the 7-position of the benzodiazepine ring, R2 is lower alkyl and A is
 17. The compound of claim 16 wherein R1 is chlorine, R2 is methyl, R3 and R4 are hydrogen and R5 is phenyl, i.e., 10-chloro-7-methyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo(3,2-d)(1, 4)benzodiazepin-6-(7H)-one.
 18. The compound of claim 16 wherein R1 is chlorine, R2 is methyl, R3 is hydrogen, R4 is chloromethyl and is joined to the 2-position of the heterocyclic ring and R5 is phenyl, i.e., 10-chloro-2-chloromethyl-2,3,5,11b-tetrahydro-7-methyl-11b-phenyloxazolo(3,2-d)(1,4)benzodiazepin-6-(7H)-one.
 19. The compound of claim 16 wherein R1 is chlorine, R2 is methyl, R3 is hydrogen, R4 is methyl joined to the 2-position of the heterocyclic ring and R5 is phenyl.
 20. 10-Chloro-2-methyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo(3, 2-d)(1,4)benzodiazepin-6(7H)-one (2,11b cis).
 21. 10-Chloro-2-methyl-2,3,5,11b-tetrahydro-11b-phenyloxazolo(3, 2-d)(1,4)benzodiazepin-6(7H)-one (2,11b trans).
 22. A process for the preparation of a compound of the formula 